ABSTRACT
Background:
Profiling circulating
cell-free DNA (
cfDNA) has become a fundamental practice in
cancer medicine, but the
effectiveness of
cfDNA at elucidating
tumor-derived molecular features has not been systematically compared to standard single-lesion
tumor biopsies in prospective cohorts of
patients. The use of
plasma instead of
tissue to guide
therapy is particularly attractive for
patients with
small cell lung cancer (SCLC), a
cancer whose aggressive
clinical course making it exceedingly challenging to obtain
tumor biopsies.
Methods:
Here, a prospective cohort of 49
plasma samples obtained before, during, and
after treatment from 20
patients with recurrent SCLC, we study
cfDNA low pass whole
genome (0.1X coverage) and
exome (130X) sequencing in comparison with
time-point matched
tumor, characterized using
exome and
transcriptome sequencing.
Results:
Direct comparison of
cfDNA versus
tumor biopsy reveals that
cfDNA not only mirrors the
mutation and copy number landscape of the corresponding
tumor but also identifies clinically relevant resistance mechanisms and
cancer driver alterations not found in matched
tumor biopsies. Longitudinal
cfDNA analysis reliably
tracks tumor response, progression, and
clonal evolution. Genomic sequencing coverage of
plasma DNA fragments around
transcription start sites shows distinct
treatment-related changes and captures the expression of key
transcription factors such as NEUROD1 and
REST in the corresponding SCLC
tumors, allowing prediction of SCLC neuroendocrine
phenotypes and
treatment responses.
Conclusions:
These findings have important implications for non-invasive stratification and subtype-specific
therapies for
patients with SCLC, now treated as a single
disease.
